This invention concerns 4,5-diamino derivatives of (1H)-pyrazoles and their use in the treatment of disorders associated with smooth muscle contraction. Such disorders include, but are not limited to, urinary incontinence, hypertension, asthma, premature labor, irritable bowel syndrome, congestive heart failure, angina, and cerebral vascular disease.
Urge urinary incontinence, the abnormal spontaneous contraction of the bladder detrusor muscle leading to a sense of urinary urgency and involuntary urine loss is currently a condition where there exists an unmet medical need (Primeau et al., Current Pharmaceutical Design, 1995, I, 391). The current treatments for this condition are the use of anticholinergics and anticholinergic/antispasmodics which have the limitations of CNS related side effects and low efficacy which leads to poor patient compliance. Hyperpolarization of bladder smooth muscle leading to the relaxation of detrusor muscle contractions may represent a novel therapeutic approach to urge urinary incontinence.
Few examples of simple 4,5-diaminopyrazoles have appeared in the chemical or patent literature. Moderhack describes the synthesis of several 4,5-diaminopyrazoles aLs intermediates towards the synthesis of 1,2,4-triazoles (Liebigs Ann. 1996, 777-9). Lewis et al. describe the synthesis of various 4,5-diaminopyrazoles (J. Heterocyclic Chem. 1983, 20, 1501-3).
The synthetic procedure used to make the diaminopyrazoles reported in this invention record is based on the procedure of Vicentini et al. (Tetrahedron 1990, 46, 5771-88 and Tetrahedron Lett. 1988, 29, 6171-2) which outlines the synthesis of 4-nitroso-5-aminopyrazoles as intermediates in the synthesis of imidazole[4,5-c]pyrazoles.
The present invention discloses compounds represented by the formula (I): 
wherein:
R1 and R2 are independently straight chain alkyl of 1 to 6 carbon atoms, branched alkyl of 3 to 6 carbons atoms, or cycloalkyl of 3 to 6 carbons atoms where R2 may be optionally substituted by F, Cl, Br, I, OH, NH2, cyano, C1-C6 alkoxy, C1-C6 alkylthio, COOH or COOC1-C6 alkyl;
R3 is an aryl or heteroaryl, optionally substituted with 1 to 4 groups selected independently from straight chain C1-C6 alkyl, branched aLkyl of 3 to 6 carbons, or a cycloalkyl of 3 to 10 carbons; C1-C6 alkoxy, cyano, F, Cl, Br, C1-C6 alkylthio, CO2R1, CONH2, OH, NH2, and NO2; wherein aryl is phenyl, naphthalene, anthracene or phenanthrene and heteroaryl is furan, thiophene, pyrrole, imidazole, oxazole, thiazole, isoxazole, pyrazole, isothiazole, oxadiazole, triazole, thiadiazole, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, naphthyridine, pterine, pyridine, pyrazine, pyrimnidine, pyridazine, pyran and triazine;
n is 0 or 1;
R4 is a straight chain alkyl group of 1 to 10 carbons atoms, a branched alkyl of 3 to 10 carbons, a cycloalkyl of 3 to 10 carbons, all of which may be optionally substituted by one or more F or Cl atoms; and all crystalline forms, enantiomers, diastereomers, and the pharmaceutically acceptable salts thereof.
It is understood that the definition of the compounds of formula (I), when R1, R2, R3, or R4, contain asymmetric carbons, encompass all possible stereoisomers and mixtures thereof which possess the activity discussed below. In particular, it encompasses racemic modifications and any optical isomers which possess the indicated activity. Optical isomers may be obtained in pure form by standard separation techniques. It is also understood that solid invention compounds or pharmaceutically acceptable salts thereof may exist in more than one crystalline form. The form obtained may be dependent upon the crystallization or recyrstallization solvent or solvent mixture, the rate of heating and/or cooling, drying conditions, and other variables. The pharmaceutically acceptable salts are those derived from such organic and inorganic acids as: lactic, citric, acetic, tartaric, succinic, maleic, malonic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, and similarly known acceptable acids. Where R2 or R3 contains a carboxyl group, salts of the compounds of this invention may be formed with bases such as alkali metals (Na, K, Li) or the alkaline earth metals (Ca or Mg).
The compounds of formula (I) have been found to relax smooth muscle. They are therefore useful in the treatment of disorders associated with smooth muscle contraction, disorders involving excessive smooth muscle contraction of the urinary tract (such as incontinence), or of the gastro-intestinal tract (such as irritable bowel syndrome), asthma, and hair loss. Furthermore, the compounds of formula (I) relax bladder smooth muscle precontracted with KCl and thus are active as potassium channel activators which render them useful for treatment of peripheral vascular disease, hypertension, congestive heart failure, stroke, anxiety, cerebral anoxia and other neurodegenerative disorders (J. R. Empfield and Keith Russell, xe2x80x9cPotassium Channel Openers,xe2x80x9d Annual Reports in Medicinal Chemistry (1995).